Construction Of Proton Sponge Type Nanoplatform For Tumor Therapy Through Autophagy Strategy

In recent years,tumor has become a severe threat to human health.It is of urgent clinical need and practical significance to develop tumor treatment methods with low toxicity and good therapeutic effect.The development of nanotechnology provides a great opportunity for the effective treatment of malignant tumors.During the treatment process,tumor cells will activate the self-protection mechanism based on autophagy to reduce the damage caused by treatment and weaken the therapeutic effect.Autophagy is a double-edged sword under treatment,and different levels of autophagy lead to different fates of tumors.On the one hand,cutting off autophagy process can be used as an effective method to increase the sensitivity of tumor cells to treatment.On the other hand,over-activated autophagy can also promote the therapeutic effect of cancer.Herein,a series of functionalized nanoplatforms based on proton sponge-type nanomaterials were constructed for effective tumor treatment through autophagy strategy.The specific contents are as follows:（1）A dual-enzyme catalyzed nanosystem was constructed to induce excessive autophagy through adenosine triphosphate（ATP）depletion strategy to achieve effective tumor elimination.This nanosystem consisted of polyvinyl pyrrolidone（PVP）-stabilized polyaniline（PANI）core,platinum（Pt）nanoparticles（NPs）decoration,and glucose oxidase（GOx）payload,showing uniform morphology and good dispersibility.After being internalized by tumor cells,PANI absorbed protons in lysosomes and caused lysosome-swelling and rupturing,facilitating the escape of NPs and compromising the cell-protective capacity of lysosome.The Pt-GOx dual-enzyme catalytic nanosystem catalyzes in situ the production of oxygen from hydrogen peroxide（H₂O₂）,which cyclically consumes glucose to cause severe ATP shortage.This energy depletion microenvironment can not only generate intracellular damage during the GOx-mediated starvation process,but also induce mitophagy through adenosine 5’-monophosphate（AMP）-activated protein kinase（AMPK）activation.The increased accumulation of damage causes excessive autophagy,overloading the degradation capacity of lysosomes and thus achieving effective elimination of tumor.In vivo data demonstrated that this nanosystem could realize tumor elimination effectively,meanwhile displaying good biocompatibility.（2）Tumor-associated macrophage（TAMs）is the most abundant immune cell in tumor microenvironment,including anti-tumor M1-type macrophages and pro-tumor M2-type macrophages.Effective control of macrophage polarization is of great significance for the activation of immune system to realize effective tumor elimination.Herein,a kind of nanocomposites based on Cu（Ⅱ）and doxorubicin（DOX）loaded polyethylene glycol acetylated dendrimers（G5-NHAc-m PEG）was constructed.G5-NHAc-m PEG has the proton sponge effect and can be used as an immunomodulator.After entering into tumor site,it can promote the polarization of tumor-associated macrophages into the M1 phenotype through deacidification and activate immune response.After cell internalization,it can deacidify,swell and rupture lysosomes,and inhibit the protective autophagy.Through Fenton-like reaction,copper ions can produce highly toxic hydroxyl radicals（·OH）,resulting in cell damage.The released DOX can further damage cells to promote the expression of H₂O₂in cells,enhancing the Fenton-like reaction.The accumulation of these lesions induces immunogenic death of tumor cells,which in turn promotes dendritic cell maturation and macrophage polarization.The G5-NHAc-m PEG-Cu（Ⅱ）-DOX nanoreactor can achieve effective tumor therapy through immune activation and autophagy regulation strategies.In vitro and in vivo data show that this combination therapy has a significant antitumor effect,showing potential in tumor treatment application in the future.